121 TSPO expression in healthy and diseased brain Table 1. TSPO cell origin in preclinical models of neurological diseases. Human use Preclinical model Microglia Astrocytes Endothelial Reference Acute inflammation LV-CNTF x x 136 AAV-TNF x x x 137 Ischemia MCAO x x 138-140 Multiple sclerosis EAE x 141,142 EAE in TSPOko x 143 CPZ x x 144,145 Alzheimer’s disease APP23 x 146 PS19 x 146 APPswe/PSEN1∆E9 x x 147,148 APPNL-G-F x 149 3xTg-AD x x 150 5xFAD x 148,151 Schizophrenia MIA x x x 152 Abbreviations: LV-CNTF = Lentivirus encoding ciliary neurotrophic factor, AAV-TNF = Adeno-associated virus encoding tumour necrosis factor, MCAO = Middle cerebral artery occlusion, EAE = Experimental autoimmune encephalomyelitis, TSPOko = 18kDa translocator protein knock-out, CPZ = Cuprizone, APP = Amyloid precursor protein, PSEN = Presenilin, 3xTg = Triple transgenic model, 5xFAD = Five AD-linked mutation model, MIA = Maternal immune activation model. subgranular layer and partially colocalizes with astrocytes but not with microglia. In the cerebellum, Purkinje cells are responsible for the expression of TSPO. Endothelial cells and pericytes of blood vessels also express TSPO. Furthermore, TSPO-positive NG2 cells were found in the spinal cord of mice142. Finally, TSPO seems to be absent from neurons and oligodendrocytes in all brain regions. However, a recent study shows a strong colocalization between TSPO and tyrosine hydroxylase (the limiting enzyme of dopamine synthesis) in the substantia nigra153. The authors concluded of that study that TSPO is present in the neurons of the dopaminergic system. CNTF and TNF Numerous studies have sought to highlight the alterations in its expression in response to either inflammatory stimuli. A first study evaluated the response to the over-expression of the ciliary neurotrophic factor (CNTF)136. The authors administered a lentivirus coding for the CNTF (containing an export sequence to be released outside the cell) via an intracerebral injection to focally induce an artificial expression of the CNTF in the brain. Two to six months after the injection, a significant increase in TSPO binding was observed on the ipsilateral side in PET imaging, which was confirmed ex vivo by western blotting and mRNA quantification. In order to characterize the cells that accounted for this upregulation, double immunofluorescence was performed for TSPO, IBA1 (a marker of microglia), and GFAP (a marker of astrocytes). In the contralateral (vehicle-treated) side, TSPO was found in microglial cells but not in astrocytes. Conversely, on the ipsilateral side, TSPO was localized in microglia as well as astrocytes indicating that CNTF induced TSPO in astrocytes. In contrast, in microglia, it is difficult to conclude whether a modification of the TSPO has taken place or not, in the absence of quantification. Indeed, although the TSPO is present on both sides of the brain (treated and control), it is possible that its level is increased in response to the chronic CNTF exposure. In a second study using a similar approach, an adenovirus encoding the sequence of the tumour necrosis factor (TNF) gene was injected into the mouse brain and analyses were performed at 3 or 5 days post injection154. Colocalization studies demonstrated the presence of TSPO in astrocytes and microglia. In addition, compared to the non-injected side, there was an increase in the number of double-positive cells for TSPO with GFAP, CD11b (a
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